The present invention relates to diamino derivatives of pyrimidines and triazines having pharmacological activity at the 5-HT7 receptor. As such, the compounds are useful for treating various central nervous system and peripheral disorders; as well as disorders of the eye.
The 5-HT7 receptor is a recent member of the growing serotonin receptor family. Both human and animal 5-HT7 receptors have recently been cloned, expressed and shown to be present in various brain areas and peripheral tissues (Eglen et al., Trend Pharmacol. Sci., 1997, 18, 104-107). The 5-HT7 receptor has been implicated in the pathophysiology of CNS disorders, such as, sleep disorders, depression, (Schwartz, et al., Adv. Int. Med. 1993, 38, 81-106), schizophrenia (Roth, et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403-1410), anxiety, obsessive compulsive disorder, migraine (Terron, Idrugs, 1998, 1, 302-310), pain and centrally and peripherally mediated hypertension (Eglen et al., supra).
Although it is not clear which serotonergic receptor(s) activity is responsible for lowering intraocular pressure (IOP), increasing blood flow and providing neuroprotection in the eye, the 5-HT7 receptor has been found in the retina, choroid and possibly the optic nerve head (May, et al., WO9959499, 4). The stimulation of the 5-HT7 receptor has caused relaxation of blood vessels in mammals such as the monkey (Leung, et al., Br. J. Pharmacol., 1996, 117, 926-930), dog (Cushing, et al., J. Pharmacol. Exp. Ther., 1996, 277, 1560-1566) and rabbit (Martin, et al., Br. J. Pharmacol., 1995, 114, 383). Stimulation of the 5-HT7 receptor may therefore improve blood flow to the optic nerve head, macula and the retina, which is believed to be beneficial in the treatment of retinal diseases such as, glaucoma, age related macular degeneration (ARMD), and diabetic retinopathy (Chiou, et al., J. Ocular Pharmacol., 1993, 9, 13-24).
The therapeutic utility of 5-HT7 receptor ligands for the treatment of CNS and ocular disorders therefore requires the discovery of therapeutic agents with a high affinity for the 5-HT7 receptor.
The present invention comprises 5-HT7 receptor antagonists and partial agonists, useful for the treatment of CNS and ocular disorders. The present invention also comprises methods of treating CNS and ocular disorders in a subject in need thereof comprising the administration of 5-HT7 antagonists and partial agonists which include compounds described in DE 2163873, DE 3717480, U.S. Pat. No. 5,491,234, WO 92/18498, U.S. Pat. No. 3,816,629, GB 1288903, WO 98/15538, DE 19704922, Mohr et al. Arch. Pharm. (Weinheim, Ger.) 1986, 319(10), 878-885, and Hadjuk et al. in J. Med. Chem. 1999, 42, 3852-3859, incorporated by reference herein.
A first embodiment of a first aspect of the present invention is a method of treating CNS and ocular disorders comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) 
or a pharmaceutically acceptable salt or hydrate thereof,
wherein
V, W and X are CH or N, provided that no more than one of V, W or X can be CH;
Y is O, S(O)m, CH2, NR9 or a covalent bond;
Z is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl, pyridinyl and phenyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, Oxe2x80x94C1-4alkyl, cyano, hydroxy, nitro, NHSO2C1-6alkyl, NR7R8, C(O)NH2 and C1-3alkylene;
m and n are each independently 0, 1 or 2;
R1 is hydrogen, halogen, C1-6alkyl, C3-7cycloalkyl, or NR7R8;
provided that
if V, W or X is CH, then R1 is not halogen or NR7R8;
if V, W and X are each N, then R1 is not hydrogen;
R2 is C1-4alkyl substituted with Zxe2x80x2, wherein
Zxe2x80x2 is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl, pyridinyl and phenyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, Oxe2x80x94C1-4alkyl, cyano, hydroxy, nitro, NHSO2C1-6alkyl, NR7R8 and C(O)NH2;
R3 is hydrogen, C1-6alkyl or C3-7cycloalkyl;
R4 and R5 are independently hydrogen or C1-6alkyl or together are C2-3alkylene;
R6 is hydrogen or C1-3alk(en)ylene
provided that
if R6 is C1-3alk(en)ylene, it is attached to Z;
R7 and R8 are independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, SO2 C1-6alkyl;
or R7 and R8 together with the nitrogen to which they are attached can form a 5 to 8 membered heterocycle;
said heterocycle optionally containing a second heteroatom selected from the group consisting of N, O and S;
said heterocycle being optionally substituted with up to three of the same or different substituents independently selected from C1-6alkyl or Oxe2x80x94C1-6alkyl; and
R9 is hydrogen or (C1-6)alkyl.
A second embodiment of the first aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first embodiment of the first aspect.
A first embodiment of a second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according the first aspect wherein
V and W are each N;
X is CH; and
R1 is H.
A second embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according the first aspect wherein
V and W are each N;
X is CH;
Z is substituted or unsubstituted phenyl; and
R1 is H.
A third embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first aspect wherein
V and W are each N;
X is CH;
Y is O or a covalent bond; and
R1 is H.
A fourth embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first aspect wherein
V and W are each N;
X is CH;
Y is O or a covalent bond;
Z is substituted or unsubstituted phenyl; and
R1 is H.
A fifth embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first aspect wherein
V and W are each N;
X is CH;
Y is O, S or a covalent bond;
Z is substituted or unsubstituted phenyl, indolyl, pyridinyl, thienyl or benzodioxolyl;
Zxe2x80x2 is substituted or unsubstituted phenyl, pyridinyl, indolyl, benzodioxolyl, thienyl. napthenyl or furanyl;
R1 is H;
R2 is C1-3alkyl substituted with Zxe2x80x2;
R3-6 are each H;
m is O; and
n is O or 1.
A sixth embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention selected from the group consisting of
N4-(3,4-Dichlorophenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N2-(2-Phenoxyethyl)-N4-[(1R)-1-phenylpropyl]pyrimidine-2,4-diamine,
N2-(2-Phenoxyethyl)-N4-[4-(trifluoromethyl)phenylmethyl]pyrimidine-2,4-diamine,
N4-(3,5-Difluorophenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N2-(2-Phenoxyethyl)-N4-[(1R)-1-phenylethyl]pyrimidine-2,4-diamine,
N4-[3-Fluoro-5-(trifluoromethyl)phenylmethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-(3,5-Dimethoxyphenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-(1-Phenylethyl)-N2-[2-(3-pyridinyl)ethyl]pyrimidine-2,4-diamine, Compound 1,
N4-(3,4-Dichlorophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N4-(2-Furanylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine, Compound 2
N4-(3-Chloro-4-methylphenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(4-Methoxyphenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N4-(3-Chlorophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-(2-Phenylethyl)-N4-[(1R)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-(2-Phenylethyl)-N4-[4-(trifluoromethyl)phenylmethyl]pyrimidine-2,4-diamine,
N4-[4-Fluoro-3-(trifluoromethyl)phenylmethyl]-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(4-Benzodioxolyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine and
N2-[2-(5-Fluoro-1H-indol-3-yl)]ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 3,
N4-(2-Furanylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine, Compound 4, and
N2-(2-Phenylethyl)-N4-(4-pyridinylmethyl)pyrimidine-2,4-diamine, Compound 5.
A seventh embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention selected from the group consisting of
N4-(3-Fluorophenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-[4-Fluoro-3-(trifluoromethyl)phenylmethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-[3-(Aminocarbonyl)phenylmethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine, Compound 6,
N4-[(1R)-1-(4-Methylphenyl)ethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-(1-Phenylethyl)-N2-(2-phenylpropyl)pyrimidine-2,4-diamine,
N4-(1-Phenylethyl)-N2-(3-phenylpropyl)pyrimidine-2,4-diamine,
N2-(2-Phenthioethyl)-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(4-Chlorophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N4-[2-(1H-Indol-3-yl)ethyl]-N2-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 7,
N2-(2-Phenylethyl)-N4-[(1R)-1-phenylpropyl]pyrimidine-2,4-diamine,
N2-[2-(3-Bromophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 8,
N2-[2-(4-Bromophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 9,
N4-(2,4-Dichlorophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(3,4-Dichlorophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N2-(lndan-2-yl)-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 10,
N2-(2-Phenylethyl)-N4-(3-pyridinylmethyl)pyrimidine-2,4-diamine, Compound 11,
N4-(1-Phenylethyl)-N2-{2-[3-(trifluoromethyl)phenyl]ethyl}pyrimidine-2,4-diamine,
N2-[2-(2-Methoxyphenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine, and
N4-(1-Phenylethyl)-N2-[2-(2-pyridinyl)ethyl]pyrimidine-2,4-diamine, Compound 12.
An eighth embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention selected from the group consisting of
N4-[(1S)-1-(4-Bromophenyl)ethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine, Compound 13,
N4-(3-Methylphenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N2-(2-Phenoxyethyl)-N4-[(1S)-1-phenylethyllpyrimidine-2,4-diamine,
N4-{3-[(Methylsulfonyl)amino]phenylmethyl}-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine, Compound 14,
N2-(2-Phenoxyethyl)-N4-[3-(trifluoromethyl)phenylmethyl]pyrimidine-2,4-diamine,
N4-(3-Chlorophenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N2-(2-Phenoxyethyl)-N4-[(1S)-1-phenylpropyl]pyrimidine-2,4-diamine,
N4-(4-Chlorophenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-(3-lodophenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine, Compound 15,
N4-(3,4-Difluorophenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-(4-Benzodioxolylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N2-(2-Phenoxyethyl)-N4-(phenylmethyl)pyrimidine-2,4-diamine,
N4-(3-Methylphenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-(3-Chloro-4-methylphenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-[1-(4-Chlorophenyl)ethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-(1-Napthalenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine, Compound 16,
N4-[(1S)-1-(1-Napthalenyl)ethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine, Compound 17,
N2-(2-Phenoxyethyl)-N4-(2-thienylmethyl)pyrimidine-2,4-diamine, Compound 18,
N4-[(1S)-1-(4-Methylphenyl)ethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-[4-(1-Methylethyl)phenylmethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N4-[2-Fluoro-5-(trifluoromethyl)phenylmethyl]-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N2-(2-Phenoxyethyl)-N4-(4-pyridinylmethyl)pyrimidine-2,4-diamine, Compound 19,
N4-(3-Chloro-4-fluorophenylmethyl)-N2-(2-phenoxyethyl)pyrimidine-2,4-diamine,
N2-(2-Phenoxyethyl)-N4-(3-pyridinylmethyl)pyrimidine-2,4-diamine, Compound 20,
N2-[2-(3-Hydroxyphenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 21,
N4-[(1S)-1-Phenylethyl]-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-(2-Phenylethyl)-N4-[(1S)-1-phenylpropyl]pyrimidine-2,4-diamine,
N2-[2-(4-Hydroxyphenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(3-Fluorophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N4-[1-(4-Fluorophenyl)ethyl]-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(2-Fluorophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N4-(2-Methoxyphenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(3-Methoxyphenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(3-Fluorophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(4-Fluorophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(3-Cyanophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 22,
N2-[2-(1-Cyclohexenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 23,
N2-[2-(3-Chlorophenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N4-[(1S)-1-(1-Napthalenyl)ethyl]-N2-(2-phenylethyl)pyrimidine-2,4-diamine, Compound 24,
N4-(1-Methyl-1-phenyl)ethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N4-(3-Iodophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine, Compound 25,
N2-(2-Phenylethyl)-N4-(phenylmethyl)pyrimidine-2,4-diamine,
N4-(3-Methylphenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N4-(4-Chlorophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N4-(3-Bromophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine, Compound 26,
N4-(3-Fluorophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-(2-Phenylethyl)-N4-(2-thienylmethyl)pyrimidine-2,4-diamine, Compound 27,
N4-[1-(4-Chlorophenyl)ethyl]-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-[2-(4-Methylphenyl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N2-(Methyl)-N2-(2-phenylethyl)-N4-(1-phenylethyl)pyrimidine-2,4-diamine,
N4-(3,4-Difluorophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N4-(4-Benzodioxolylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N4-(2-Chlorophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N4-(3-Chloro-4-fluorophenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N4-(3-Methoxyphenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N4-(4-Methoxyphenylmethyl)-N2-(2-phenylethyl)pyrimidine-2,4-diamine,
N2-(2-Phenylethyl)-N4-[3-(trifluoromethyl)phenylmethyl]pyrimidine-2,4-diamine,
N2-[2-(1H-Indol-1-yl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 28,
N4-(1-Phenylethyl)-N2-[2-(2-thienyl)ethyl]pyrimidine-2,4-diamine, Compound 29,
N2-[2(1H-Indol-3-yl)ethyl]-N2-(methyl)-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 30 and
N2-[2-(6-Fluoro-1H-indol-3-yl)ethyl]-N4-(1-phenylethyl)pyrimidine-2,4-diamine, Compound 31.
A ninth embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according the first aspect wherein
V and W are each N;
X is CH; and
R1 is C1-6alkyl or C3-7cycloalkyl.
An tenth embodiment of the second aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention selected from the group consisting of
N2-[2-(3-Fluorophenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-[2-(3-Methoxyphenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-[2-(3-Bromophenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-[2-(3-Cyanophenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-[2-(4-Chlorophenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-[2-(4-Methylphenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-[2-(2-Methoxyphenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-[2-(3,5-Dimethoxyphenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-[2-(3-Bromo-4-methoxyphenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine,
N2-[2-(4-Methoxyphenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine, and
N2-[2-(3-Acetamidophenyl)ethyl]-6-methyl-N4-[(1S)-1-phenylethyl]pyrimidine-2,4-diamine.
A first embodiment of a third aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first aspect wherein
X and W are each N;
V is CH; and
R1 is H.
An second embodiment of the third aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention said compound being N4-[2-(4-Fluorophenoxy)ethyl]-N2-(1-phenylethyl)pyrimidine-2,4-diamine.
A first embodiment of a fourth aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first aspect wherein
X and V are each N;
W is CH; and
R1 is H.
A second embodiment of the fourth aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention selected from the group consisting of
N4-[2-(4-Aminophenyl)ethyl]-N6-[(1S)-1-phenylethyl]pyrimidine-4,6-diamine, and
N4-[2-(4-Bromoophenyl)ethyl]-N6-[(1S)-1-phenylethyl]pyrimidine-4,6-diamine.
A third embodiment of the fourth aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention selected from the group consisting of
N4-[2-(4-Hydroxyphenyl)ethyl]-N6-[(1S)-1-phenylethyl]pyrimidine-4,6-diamine, and
N4-[2-(4-Fluorophenoxy)ethyl]-N6-[(1S)-1-phenylethyl]pyrimidine-4,6-diamine, Example 16.
A first embodiment of a fifth aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first embodiment of the first aspect wherein
V, W and X are each N; and
R1 is NH2.
A second embodiment of a fifth aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) according to the first embodiment of the first aspect wherein
V, W and X are each N;
R1 is NH2; and
Y is O.
A second embodiment of the fifth aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention selected from the group consisting of
N2-[2-(4-Chlorophenyl)ethyl]-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 32,
N2-[2-(3,4-Dichlorophenyl)ethyl]-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 33,
N2-[(1S)-1-(4-Bromophenyl)ethyl]-N4-[2-(4-methylphenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 34,
N2-[(1S)-1-Phenylpropyl]-N4-(2-phenylpropyl)-1,3,5-triazine-2,4,6-triamine, Compound 35,
N2-[(1S)-1-Phenylpropyl]-N4-[2-(3-(trifluoromethyl)phenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 36,
N2-[(1S)-1-Phenylethyl]-N4-(2-phenylpropyl)-1,3,5-triazine-2,4,6-triamine, Compound 37,
N2-[(1S)-1-(1-Napthalenyl)ethyl]-N4-[2-(phenylamino)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 38, and
N2-[2-(4-Bromophenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 39.
A third embodiment of the fifth aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention selected from the group consisting of
N2-[2-(Phenoxy)ethyl]-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 40,
N2-[2-(Phenoxy)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 41, Example 19-20,
N2-[(1S)-1-(1-Napthyl)ethyl]-N4-[2-(phenoxy)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 42,
N2-[2-(4-Fluorophenoxy)ethyl]-N4-[1-(4-fluorophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 43,
N2-[2-(4-Fluorophenoxy)ethyl]-N4-[(1S)-1-(4-fluorophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 44,
N2-[2-(4-Fluorophenoxy)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 45,
N2-[2-(4-Fluorophenoxy)ethyl]-N4-[(1R)-1-(4-fluorophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 46,
N2-[2-(3,4-Difluorophenoxy)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 47,
N2-[2-(2-Fluorophenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 48,
N2-[2-(4-Methylphenyl)ethyl]-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 49,
N2-[2-(4-Chlorophenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 50,
N2-[2-(2-Fluorophenyl)ethyl]-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 51,
N2-[2-(3-Methoxyphenyl)ethyl]-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 52,
N2-[(1S)-1-Phenylethyl]-N4-{2-[3-(trifluoromethyl)phenyl]ethyl}-1,3,5-triazine-2,4,6-triamine, Compound 53,
N2-[2-(3-Methoxyphenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 54,
N2-[2-(3-Cyanophenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 55,
N2-[(1S)-1-(1-Napthalenyl)ethyl]-N4-(2-phenylethyl)-1,3,5-triazine-2,4,6-triamine, Compound 56,
N2-[2-(1-Cyclohexenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 57
N2-[2-(3-Chlorophenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 58 and
N2-[2-(4-Chlorophenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 59.
A fourth embodiment of the fifth aspect of the present invention is a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (I) as described in the first aspect of the invention selected from the group consisting of
N2-[(1S)-1-Phenylethyl]-N4-(2-phenylethyl)-1,3,5-triazine-2,4,6-triamine, Compound 60,
N2-[2-(3-Fluorophenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 61,
N2-[2-(3-Chlorophenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 62,
N2-[2-(3-Fluorophenyl)ethyl]-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 63,
N2-[2-(4-Fluorophenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 64,
N2-2-Phenylethyl-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 65,
N2-[2-(3-Bromophenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 66,
N2-[2-(4-Fluorophenyl)ethyl]-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 67,
N2-[(1S)-1-(4-Bromophenyl)ethyl]-N4-[2-(3-fluorophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 68,
N2-[2-(3-Chlorophenyl)ethyl]-N4-[(1S)-1-phenylpropyl]-1,3,5-triazine-2,4,6-triamine, Compound 69,
N2-[(1S)-1-(4-Bromophenyl)ethyl]-N4-[2-(4-fluorophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 70,
N2-[2-(3,4-Dichlorophenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 71,
N2-[2-(4-Methylphenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 72,
N2-[2-(3-Hydroxyphenyl)ethyl]-N4-[(1S)-1-phenylethyl]-1,3,5-triazine-2,4,6-triamine, Compound 73,
N2-[2-(4-Fluorophenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]--1,3,5-triazine-2,4,6-triamine, Compound 74,
N2-[2-(4-Hydroxyphenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 75,
N2-[2-(2-Fluorophenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 76,
N2-[2-(3-Methoxyphenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 77,
N2-[2-(4-Aminophenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 78,
N2-[2-(4-Methylphenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 79,
N2-[2-(4-Hydroxy-3-methoxyphenyl)ethyl]-N4-[(1S)-1-(4-nitrophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Compound 80,
N2-[(1S)-1-(4-Fluorophenyl)ethyl]-N4-[2-(4-fluorophenyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Example 17,
N2-[(1S)-1-(4-Fluorophenyl)ethyl]-N4-[2-(2-pyridinyl)ethyl]-1,3,5-triazine-2,4,6-triamine, Example 18, 21, and
N2-(2-Chlorophenylmethyl)-N4-(2-phenylethyl)-1,3,5-triazine-2,4,6-triamine.
A first embodiment of a sixth aspect of the present invention are compounds of Formula (I) 
or a pharmaceutically acceptable salts or hydrates thereof,
wherein
V, W and X are each N, or V and X are each N and W is CH;
Y is O, S(O)m, CH2, NR9 or a covalent bond;
Z is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl, pyridinyl and phenyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, Oxe2x80x94C1-4alkyl, cyano, hydroxy, nitro, NH SO2 C1-6alkyl, NR7R8, C(O)NH2 and C1-3alkylene;
m and n are each independently 0, 1 or 2;
R1 is hydrogen, halogen or NR7R8;
provided that
if W is CH, then R1 is not halogen or NR7R8;
if V, W and X are each N, then R1 is not hydrogen;
R2 is C1-4alkyl substituted with Zxe2x80x2, wherein
Zxe2x80x2 is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl, pyridinyl and phenyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, Oxe2x80x94C1-4alkyl, cyano, hydroxy, nitro, NH SO2 C1-6alkyl, NR7R8 and C(O)NH2;
R3 is hydrogen, C1-6alkyl or C3-7cycloalkyl;
R4 and R5 are independently hydrogen or C1-6alkyl or together are C2-3alkylene;
R6 is hydrogen or C1-3alk(en)ylene
provided that
if R6 is C1-3alk(en)ylene, it is attached to Z;
R7 and R8 are independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, SO2 C1-6alkyl;
or R7 and R8 together with the nitrogen to which they are attached form a 5 to 8 membered heterocycle;
said heterocycle optionally containing a second heteroatom selected from the group consisting of N, O and S;
said heterocycle being optionally substituted with up to three of the same or different substituents independently selected from C1-6alkyl or Oxe2x80x94C1-6alkyl; and
R9 is hydrogen or (C1-6)alkyl.
A second embodiment of the sixth aspect of the present invention are compounds of formula (I) according to the first embodiment of the sixth aspect, wherein
V, W and X are each N.
A third embodiment of the sixth aspect of the present invention are compounds of formula (I) according to the first embodiment of the sixth aspect, wherein
V and X are each N and W is CH.
A fourth embodiment of the sixth aspect of the present invention are compounds of formula (I) according to the first embodiment of the sixth aspect, wherein
Y is NR9.
A fifth embodiment of the sixth aspect of the present invention are compounds of formula (I) according to the first embodiment of the sixth aspect, wherein
Z is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl and pyridinyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, Oxe2x80x94C1-4alkyl, cyano, hydroxy, nitro, NH SO2 C1-6alkyl, NR7R8, C(O)NH2 and C1-3alkylene; and
Zxe2x80x2 is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl and pyridinyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, Oxe2x80x94C1-4alkyl, cyano, hydroxy, nitro, NH SO2 C1-6alkyl, NR7R8 and C(O)NH2.
A sixth embodiment of the sixth aspect of the present invention are compounds of formula (1) according to the first embodiment of the sixth aspect, wherein
Zxe2x80x2 is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl and pyridinyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, Oxe2x80x94C1-4alkyl, cyano, hydroxy, nitro, NH SO2 C1-6alkyl, NR7R8 and C(O)NH2.
A seventh embodiment of the sixth aspect of the present invention are compounds of formula (I) according to the first embodiment of the sixth aspect, wherein
Z is selected from the group consisting of benzodioxolyl, cyclohexenyl, furanyl, indolyl, napthalenyl, thienyl and pyridinyl;
optionally substituted with one to five groups, the same or different independently selected from the group consisting of halogen, C1-4alkyl, C1-4haloalkyl, Oxe2x80x94C1-4alkyl, cyano, hydroxy, nitro, NH SO2 C1-6alkyl, NR7R8, C(O)NH2 and C1-3alkylene.
A first embodiment of a seventh aspect of the present invention are compounds of formula (Ia) 
and pharmaceutically acceptable salts and solvates thereof,
wherein
R1 is phenyl optionally substituted with one or more of the same or different halogens; and
R2 is phenyl or pyridyl optionally substituted with one or more of the same or different halogens.
A second embodiment of the seventh aspect of the present invention are compounds according to the first embodiment of the seventh aspect of the present invention wherein
R1 is phenyl optionally substituted with one or more of the same halogens; and
R2 is phenyl or pyridyl optionally substituted with one or more of the same halogens.
A third embodiment of the seventh aspect of the present invention are compounds according to the first embodiment of the seventh aspect of the present invention wherein
R1 is phenyl optionally substituted with one halogen; and
R2 is phenyl or pyridyl optionally substituted with one halogen.
A fourth embodiment of the seventh aspect of the present invention are compounds according to the first embodiment of the seventh aspect of the present invention wherein
R1 is phenyl optionally substituted with fluoro; and
R2 is phenyl or pyridyl optionally substituted with fluoro.
A fifth embodiment of the seventh aspect of the present invention are compounds according to the first embodiment of the seventh aspect of the present invention wherein
R1 is unsubstituted phenyl; and
R2 is monofluoro-phenyl or unsubstituted pyridyl.
A sixth embodiment of the seventh aspect of the present invention are compounds according to the first embodiment of the seventh aspect of the present invention wherein R2 is unsubstituted 4-pyridyl.
A seventh embodiment of the seventh aspect of the present invention are compounds according to the first embodiment of the seventh aspect of the present invention selected from the group consisting of (S,S)-trans-N-[2-(4-Fluoro-phenyl)-cyclopropylmethyl]-Nxe2x80x2-(1-phenyl-ethyl)-[1,3,5]triazine-2,4,6-triamine, (S,S)-trans-N-[2-(2-Fluoro-phenyl)-cyclopropylmethyl]-Nxe2x80x2-(1-phenyl-ethyl)-[1,3,5]triazine-2,4,6-triamine, (xc2x1)-trans-N-(1-Phenyl-ethyl)-Nxe2x80x2-(2-pyridin-4-yl-cyclopropylmethyl)-[1,3,5]triazine-2,4,6-triamine, (xc2x1)-trans-N-[2-(2-Fluoro-phenyl)-cyclopropylmethyl]-Nxe2x80x2-(1-phenyl-ethyl)-[1,3,5]triazine-2,4,6-triamine, (S,S)-trans-N-[2-(4-Fluoro-phenyl)-cyclopropylmethyl]-Nxe2x80x2-[1-(4-fluoro)phenyl-ethyl]-[1,3,5]triazine-2,4,6-triamine and (xc2x1)-trans-N-[2-(4-Fluoro-phenyl)-cyclopropylmethyl]-Nxe2x80x2-(1-phenyl-ethyl)-[1,3,5]triazine-2,4,6-triamine.
Embodiments of an eighth aspect of the present invention comprise a method of treating CNS and ocular disorders comprising administration to a subject in need thereof an effective amount of a compound of Formula (Ia) as described in the seventh aspect of the present invention.
Embodiments of a ninth aspect of the present invention comprise a method of treating sleeping disorders, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, ocular disorders and/or centrally and peripherally mediated hypertension comprising administration to a subject in need thereof an effective amount of a compound of Formula (Ia) as described in the seventh aspect of the present invention.
Embodiments of a tenth aspect of the present invention comprise a method of inhibiting methyltransferase proteins comprising administration of an effective amount of a compound of Formula (Ia) as described in the seventh aspect of the present invention.
The description of the invention herein should be construed in congruity with the laws and principals of chemical bonding. An embodiment or aspect which depends from another embodiment or aspect, will describe only the variables having values and provisos that differ from the embodiment or aspect from which it depends. Thus, for example, an embodiment which reads xe2x80x9cthe compound of formula (I) according to the nth aspect of the invention, wherein W is CHxe2x80x9d should be read to include all remaining variables with values defined in the nth aspect and should be read to further include all the provisos, unless otherwise indicated, pertaining to each and every variable in the nth aspect.
As used herein the term xe2x80x9cC1-4alkylxe2x80x9d may be a straight or branched chain having from 1 to 4 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. As used herein the term xe2x80x9cC1-6alkylxe2x80x9d may be a straight or branched chain having from 1 to 6 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, n-hexyl, etc. The term xe2x80x9cC3-7cycloalkylxe2x80x9d are cyclic alkanes with or without branching having from 3 to 7 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl etc. The term xe2x80x9cC2-3alkylenexe2x80x9d can be a straight or branched chain having from 2 to 3 carbon atoms and includes xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, and xe2x80x94CH(CH3)CH2xe2x80x94. The term xe2x80x9calk(en)ylenexe2x80x9d can mean alkenylene or alkylene. The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo.
It is to be understood that the present invention includes stereoisomers, e.g. optical isomers including individual enantiomers and mixtures of enantiomers which can arise as a consequence of structural asymmetry due to the presence of an asymmetric carbon atom which may be incorporated in some examples of the Formula I compounds. The compounds of the present invention may be prepared enantioselectively, or alternatively, the separation of the individual stereoisomers can be accomplished by application of various methods which are well known to practitioners in the art.
For medicinal use, the pharmaceutically acceptable acid addition salts of Formula (I) compounds are included in the invention. Such salts are those in which the anion does not contribute significantly to toxicity or pharmacologic activity of the organic cation. These salts may be preferred in some cases. The acid addition salts may be prepared from inorganic or organic acids, e.g. salts with acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, maleic, acetic, citric, succinic, tartaric, benzoic, fumaric, mandelic, p-toluenesulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic and the like. The compounds of the present invention may be hydrated or non-hydrated.
The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of this invention may also be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, all using using dosage forms well known to those of ordinary skill in the pharmaceutical arts. The compounds can be administered alone but generally will be administered with a pharmaceutical carrier selected upon the basis of the chosen route of administration and standard pharmaceutical practice.
Compounds of this invention can also be administered in intranasal form by topical use of suitable intranasal vehicles, or by transdermal routes, using transdermal skin patches. When compounds of this invention are administered transdermally the dosage will be continuous throughout the dosage regimen.
The compounds of this invention can also be administered to the eye, preferrably as a topical opthalmic formulation. The opthalmic formulation may be a sterile opthalmic suspension or solution, formed by combining a compound of this invention with opthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water. Opthalmic solution formulations may be prepared by dissolving a compound of this invention in a physiologically acceptable isotonic buffer which may include an opthalmologically acceptable surfactant to assist in dissolving the compound. The opthalmic solution may also contain an agent to increase viscosity such as hydroxymethylcellulose or a gelling agent such as gellan or xanthan gum. The compounds of this invention can also be combined with a preservative and an appropriate vehicle such as mineral oil or liquid lanolin to provide an opthalmic ointment. Opthalmic gels can be prepared by suspending a compound of this invention in a hydrophilic base such as carbopol-940. The preferred opthalmic formulation is the opthalmic suspension or solution. The opthalmic suspension or solution will contain approximately 0.01% to 5% by weight of a compound of this invention and will have a pH of about 5 to 8. The opthalmic suspension or solution can be topically administered by delivering 1 to 2 drops of the formulation to the surface of the eye. This dosage can be administered between 1 to 4 times daily at the discretion of the clinician.
The dosage can vary within wide limits and will have to be adjusted to the individual requirements in each particular case. By way of general guidance, the daily oral dosage can vary from about 0.01 mg to 1000 mg, 0.1 mg to 100 mg, or 10 mg to 500 mg per day of a compound of Formula (I) or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
The compounds of Formula I can be synthesized as shown in Schemes 1-3. Specific reactions employed for the preparation of compounds of Formula I are described below. Many of the reactions are conventional and their modification for adaptation for specific compounds of Formula I would be known to one skilled in the art of organic synthesis. It will be understood by one skilled in the art that the functionality present on the molecule should be consistent with the desired transformation and that modification of the order of the synthetic steps may be necessary to prepare a compound of the invention. Preferred methods for the synthesis of Formula I compounds include, but are not limited to, the methods described below. The abbreviations used in the description and examples are conventional abbreviations well-known to those skilled in the art. Some of the abbreviations used are as follows:

Compounds of Formula I may be prepared, as shown in Scheme 1, by sequential displacement of leaving groups on a heterocycle, V, with appropriate amines, IV and II, in the presence of a base in an appropriate solvent. Examples of useful leaving groups, LG, on heterocycle V include, but are not limited to, Cl, Br, I, alkylsulfonate, arylsulfonate or perhaloalkylsulfonate. Useful bases include, but are not limited to, an excess of the amine itself (IV or 11), metal carbonates such as K2CO3 or CsCO3, hindered alkoxides such as potassium t-butoxide, or non-nucleophilic tertiary organic amines such as triethylamine, N,N-diisopropylethylamine or 4-methylmorpholine. Typical solvents include, but are not limited to, aprotic solvents such as NMP, DMF, dimethylacetamide, CH3CN, dioxane, CH2Cl2, THF or protic solvents such as MeOH, EtOH, isopropanol, butanol, amyl alcohol, cyclohexanol and ethoxyethoxyethanol. The temperature range used for both steps in Scheme 1 is between xe2x88x9210xc2x0 C. and 200xc2x0 C. It is understood by one skilled in the art that mixtures of regioisomers of intermediate III may be obtained from the initial displacement reaction in Scheme 1. It is also understood by one skilled in the art that the regioisomers thus obtained can be separated and purified by recrystallization or column chromatography and then further reacted to give compounds of Formula I.
In a more detailed description of the procedure, one molar equivalent of an optionally substituted pyrimidine, such as 4,6-dichloropyrimidine or 2,4-dichloropyrimidine, and one molar equivalent of a tertiary amine such as triethylamine, diisopropylethylamine or 4-methylmorpholine and one molar equivalent of an amine, ZY(CH2)nCH(R5)CH(R6)NH(R4), are combined in a solvent such as EtOH and maintained between xe2x88x9210xc2x0 C. to 200xc2x0 C. for a period of 1 to 48 hours. A preferred temperature range for this step is between 0xc2x0 C. and 80xc2x0 C.
The reaction mixture can be filtered and the filtrate concentrated under reduced pressure to provide the intermediate product, III. Alternatively, the reaction mixture can be diluted with an organic solvent such as CH2Cl2 or EtOAc. The organic layer can then be washed with water and brine, dried over magnesium sulfate or sodium sulfate, filtered, and concentrated under reduced pressure to provide the intermediate product. The intermediate product may be purified by recrystallization or by chromatography on silica gel using an eluant such as EtOAc, hexanes, CH2Cl2, chloroform, Et2O, MeOH, EtOH or mixtures thereof.
The second step of the synthesis consists of combining one molar equivalent of the intermediate product, III, such as a 2-chloro-4-aminopyrimidine, 4-chloro-2-aminopyrimidine or 4-chloro-6-aminopyrimidine derivative, with either two or more molar equivalents of amine, R3R2NH, or one molar equivalent of amine, R3R2NH, and one molar equivalent of a tertiary amine such as triethylamine, diisopropylethylamine, or 4-methylmorpholine, in a solvent such as NMP or ethoxyethoxyethanol for a period of 1 to 48 hours at reaction temperatures between xe2x88x9210xc2x0 C. and 200xc2x0 C.
The reaction mixture is then allowed to cool to room temperature. In cases where more than two equivalents of amine, R3R2NH, were used, the mixture can be stirred with polystyrene-bound aldehyde resin in order to scavenge the excess amine. (The aldehyde resin was prepared by treating chloromethyl polystyrene resin (Merrifield resin) with 1.4 molar equivalents of sodium bicarbonate in anhydrous DMSO at 160xc2x0 C. for 24 hours. The resin was then collected by filtration, washed with DMSO, H2O, 1:1 DMSO/H2O, DMF, acetone, EtOH, CH2Cl2, Et2O and MeOH, then was dried under vacuum). The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The crude material can be purified by either chromatography on silica gel using an eluant such as CH2Cl2, hexane, EtOAc, chloroform, Et2O, MeOH, EtOH or mixtures thereof. Alternatively, the crude material can be purified by reverse phase HPLC on C-18 using eluent such as MeOH, CH3CN, H2O, TFA or mixtures thereof. If necessary, further purification of the compound can be accomplished by recrystallization. 
Other compounds of Formula I may be prepared, as shown by Scheme 2, by sequential displacement of leaving groups on a substituted heterocycle, XIV, which has been attached to an insoluble polymer support, XV, with appropriate amines, IV and II, in the presence of a base in an appropriate solvent. Examples of useful leaving groups, LG, on heterocycle XIV include, but are not limited to, Cl, Br, I, alkylsulfonate, arylsulfonate or perhaloalkylsulfonate. Useful bases include, but are not limited to, an excess of the amine itself (IV or II), metal carbonates such as K2CO3 or CsCO3, or non-nucleophilic tertiary organic amines such as triethylamine, N,N-diisopropylethylamine or 4-methylmorpholine. Typical solvents include, but are not limited to dichloroethane, DMF and NMP and the reactions are typically carried out between 0xc2x0 C. and 100xc2x0 C. The resulting resin bound compound, XI, is treated with acid, such as TFA, in an appropriate solvent such as CH2Cl2, then the resin is filtered and rinsed with solvent. The filtrate and combined rinsing solution is then combined and concentrated under reduced pressure to afford compounds of Formula I wherein R1=NH2. 
Some compounds of Formula I may be prepared, as shown in Scheme 3, by sequential displacement of leaving groups on a heterocycle, XIV, with appropriate amines, in the presence of base in an appropriate solvent. The leaving groups, solvents, bases, and techniques used for isolating the intermediate products as well as the compounds of Formula I are the same as previously described for Scheme 1.
In a more detailed description of the procedure, one molar equivalent of a heterocycle, XIV, such as cyanuric chloride, and one molar equivalent of a tertiary amine such as triethylamine, diisopropylethylamine, or 4-methylmorpholine, and one molar equivalent of an amine, R3R2NH, are combined in a solvent such as THF and maintained between xe2x88x9210xc2x0 C. to 30xc2x0 C. for a period of 1 to 48 hours. The reaction mixture is concentrated under reduced pressure, the residue is dissolved in a solvent, such as EtOAc or CH2Cl2, and then extracted with 1 N HCl, H2O, and brine. The organic layer is dried, filtered, and concentrated to afford intermediate, XXIII. Intermediate XXIII can be combined with an amine, R1H, such as ammonium hydroxide, dimethylamine or morpholine in a solvent such as THF in the presence of base at ambient temperature for a period of 1 to 48 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in a solvent such as CH2Cl2 or EtOAc then extracted with H2O. The organic layer is dried, filtered and concentrated in vacuo to afford intermediate, XXII. Intermediate XXII can be combined with either two or more molar equivalents of amine, ZY(CH2)nCH(R5)CH(R6)NH(R4), or one molar equivalent of amine, ZY(CH2)nCH(R5)CH(R6)NH(R4), and one molar equivalent of a tertiary amine such as triethylamine, diisopropylethylamine, or 4-methylmorpholine, in a solvent such as THF or NMP at reaction temperatures between approximately 30xc2x0 C. and 80xc2x0 C. for 1 to 48 hours. The reaction may then be concentrated under reduced pressure and the residue dissolved in a solvent such as CH2Cl2 or EtOAc. The organic layer can be extracted with H2O, dried, and concentrated to afford compound of Formula I as the free base. Alternatively, the organic layer can be washed with 1 N HCl and solids which precipitate from the organic layer can be collected by filtration. The solids can be washed with H2O and CH3CN, triturated with hot CH3CN, collected by filtration, and dried to afford compounds of Formula I as the hydrochloride salt.
The amines, ZY(CH2)nCH(R5)CH(R6)NH(R4) and R3R2NH, employed in the synthesis of Formula I compounds, are either commercially available or can be readily synthesized by the methods shown in Schemes 4-6. 
Racemic mixtures of an amine may be resolved by methods known to those skilled in the art and the chiral amine may then be used in the synthesis. A typical preparation of an amine, as shown in Scheme 4, may be accomplished by refluxing an acetonitrile solution of an aniline, phenol, thiophenol or amino, thio or hydroxyl bearing heterocycle with chloroacetonitrile in the presence of a base, such as potassium carbonate. The resulting acetonitrile derivative may then be reduced, with a reducing agent such as alane, to provide an amine of Formula IV wherein n=0, R4, R5, and R6 are H. Alternatively, the amines can be prepared as shown in Scheme 5, by alkylating a substituted aniline, phenol, thiophenol or amino, thio or hydroxyl bearing heterocycle with a protected aminoalkylhalide to provide protected alkylamine derivatives. A preferred protecting group (PG) is the tert-Butoxycarbonyl (Boc) group. These derivatives can then be deprotected to provide amine intermediates of Formula IV. For example, when PG is Boc, treatment of the protected intermediate with an acid such as trifluoroacetic acid or hydrochloric acid provides amines of Formula IV.
A third method used to synthesize amine intermediates is shown in Scheme 6 and consists of the preparation of an oxime which is then reduced to provide the amine intermediate, II.
All of the compounds were synthesized by using the preceding general methodologies and were characterized by LC/MS. The following tables provide retention times and the mass observed for selected compounds of the invention. For LC/MS analysis all Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis detector and Mass Spectrometry (MS) data were determined with a Micromass Platform for LC in electrospray mode. The various LC/MS methods used for the analysis of the compounds are given below. Purification of compounds by preparative HPLC was accomplished using either a Shimadzu LC-8A liquid chromatograph using a SPD-10AV UV-Vis detector and equipped with FRC-10A fraction collectors or a Varian Prostar Model 215 liquid chromatograph using a Rainin Dynamax UV-Vis detector. A typical preparative HPLC method is given below. In the LC/MS methods and the preparative HPLC method Solvent A is 10% MeOH/90% H2O/0.1% TFA and Solvent B is 90% MeOH/10% H2O/0.1% TFA.
Preparative HPLC Method
Column: YMC ODS S5 30xc3x97100 mm
Gradient: Linear gradient from 100% Solvent A 0% Solvent B to 0% Solvent A/100% Solvent B
Gradienttime: 11 minutes
Hold time: 5 minutes
Flow rate: 49 mL/min
Detector Wavelength: 254 nm
LC/MS Method A
Column: YMC ODS S5 4.6xc3x9750 mm Ballistic
Gradient: Linear gradient from 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B
Gradient time: 3 minutes
Hold time: 1 minute
Flow rate: 4 mL/min
Detector Wavelength: 220 nm
LC/MS Method B
Column: YMC ODS-A S7 3.0xc3x9750 mm
Gradient: Linear gradient from 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B
Gradient time: 2 minutes
Hold time: 1 minute
Flow rate: 5 mL/min
Detector Wavelength: 220 nm